N,N'-bis(2,4,6-triisopropylphenyl)methanediimine

Skin sensitisation

Administrative data

Endpoint:

skin sensitisation, other

Remarks:

SAR-Profiling of structural alerts for skin sensitisation (OECD QSAR Toolbox)

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Study period:

2018-11-13

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

1. SOFTWARE
OECD QSAR Toolbox v4.2

2. MODEL (incl. version number)
please refer to 'Attached justification'

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
CC(C)c1cc(C(C)C)c(N=C=Nc2c(cc(cc2C(C)C)C(C)C)C(C)C)c(c1)C(C)C

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
please refer to 'Attached justification'

5. APPLICABILITY DOMAIN
please refer to 'Attached justification'


6. ADEQUACY OF THE RESULT
These profiling results are used in a weight-of-evidence approach to assess the skin sensitising potential of the registered substance. The selected profilers detect structural alerts, which are associated with the potential to bind to or interact with proteins. The binding to skin proteins is the first step of the Adverse Outcome Pathway for skin sensitisation. Binding to skin proteins is essential to induce a specific memory T-cell response associated with skin sensitisation.

Data source

Reference

Reference Type:

other: Website

Title:

OECD QSAR Toolbox v4.2

Year:

2018

Bibliographic source:

https://www.qsartoolbox.org/home

Report date:

2018

Materials and methods

Test guideline

Guideline:

other: REACH Guidance on QSARs R.6

Version / remarks:

Profiling was performed with the QSAR Toolbox Version 4.2

Principles of method if other than guideline:

- Software tool(s) used including version: OECD QSAR Toolbox v.4.2
- Model(s) used: please refer to 'Attached justification'
- Model description: see field 'Attached justification'
- Justification of QSAR prediction: see field, 'Attached justification'

Test material

Test material information

Constituent 1

Reference substance name:

N,N'-bis[2,4,6-tris(propan-2-yl)phenyl]methanediimine

EC Number:

815-171-4

Cas Number:

300382-79-0

Molecular formula:

C31H46N2

IUPAC Name:

N,N'-bis[2,4,6-tris(propan-2-yl)phenyl]methanediimine

Specific details on test material used for the study:

CC(C)c1cc(C(C)C)c(N=C=Nc2c(cc(cc2C(C)C)C(C)C)C(C)C)c(c1)C(C)C

Results and discussion

In vivo (LLNA)

Results

Remarks on result:

positive indication of skin sensitisation based on QSAR/QSPR prediction

Any other information on results incl. tables

Table 1: OECD QSAR Toolbox 4.2 profiling results for skin sensitisation

QSAR Toolbox protein binding profiler	Result	within applicability domain of profiler
General Mechanistic Profilers
Protein binding by OASIS v1.5^1	Mechanistic Domain: Acylation Mechanistic Alert: Acyl transfer via nucleophilic addition reaction Structural Alert: Carbodiimides	yes
Protein binding by OECD v2.3^2	Mechanistic Domain: Acylation Mechanistic Alert: Isocyanate and Related Chemicals Structural Alert: Carbodiimides	yes
Protein binding potency Cys (DPRA 13%) v.01^3		no
Protein binding potency GSH v3.4^4		no
Protein binding potency Lys (DPRA 13%) v.01^3		no
Endpoint specific Profilers
Keratinocyte gene expression v2.0^5		no
Protein binding alerts for skin sensitisation according to GHS v1.1	Skin sensitisation Category 1A Structural Alert: Carbodiimides	yes
Protein binding alerts for skin sensitisation by OASIS v1.6^1	Mechanistic Domain: Acylation Mechanistic Alert: Acyl transfer via nucleophilic addition reaction Structural Alert: Carbodiimides	yes
Protein Binding Potency h-CLAT v1.0^6	no alert found	yes

¹Proposed mechanistic domains: Acylation (Ac), Ionic Interaction (II), Michael addition (MA), Nucleophilic addition (NA), Radical reactions (RR), Schiff base formation (SB), Nucleophilic substitution type 1 (SN1), Nucleophilic substitution type 2 (SN2), Nucleophilic substitution type 2 ionic (Sn2i), Nucleophilic aromatic substitution (SNAr), , Nucleophilic vinylic substitution (SnV)

²Proposed mechanistic domains: Acylation (Ac), Michael addition (MA), Schiff base formation (SB), Nucleophilic substitution type 2 (SN2), Nucleophilic aromatic substitution (SNAr)

³Peptide reactivity is reported as percent peptide depletion and is separated into three potency categories: DPRA above 21% (DPRA 13%) as reactive, DPRA less than 9% (DPRA 13%) as not reactive and Grey zone 9-21% (DPRA 13%)

⁴Thiol reactivityexpressed by the in chemico RC50 value for binding at the thiol group of glutathione (GSH). All the chemicals have two common electrophilic mechanisms of interaction with GSH – interaction via SN2 and interaction via Michael addition (MA) mechanism. Classification of potency categories is as follows: extremely reactive (RC50 < 0.099 mmol/L); highly reactive (RC50 = 0.100 – 0.990 mmol/L); moderately reactive (RC50 = 1.000 – 15.000 mmol/L); slightly reactive (RC50 = 16.000 – 70.000 mmol/L); suspect (RC50 = 71.000 – 135.000).

⁵Classification of categories depends on the EC1.5 values (the concentration eliciting a 1.5-fold gene induction) and is as follows: chemicals having very high gene expression (EC1.5< = 15 µM); high gene expression (EC1.5 = 15 – 50 µM); moderate gene expression (EC1.5 = 50 – 100 µM); low gene expression (EC1.5 = 100 – 1999 µM).

⁶The profile contains 30 structural alerts extracted from 223 chemicals with positive/negative data values derived from the human cell line activation (h-CLAT) assay.

Applicant's summary and conclusion

Interpretation of results:

study cannot be used for classification

Conclusions:

Profiling of the registered substance with the OECD QSAR Toolbox v4.2 revealed structural alerts associated with protein binding. The structural alert is the carbodiimide which is associated with the mechanism 'Acyl transfer via nucleophilic addition reaction'. Protein binding is a crucial step in the initiation of skin sensitisation. However, the carbodiimide group is surrounded by two triisopropylphenyl rings making it hardly accessible for skin proteins. Thus, it is questionable, if the molecule reacts with skin proteins in vivo. That the carbodiimide group is covered within the molecule is also supported by the fact that the registered substance is not skin irritating (OECD 439, Bayer, 2018), although the carbodiimide group is associated with skin irritation.

Executive summary:

The substance was profiled for skin sensitisation by the relevant profilers with the OECD QSAR Toolbox v4.2. The profiling results indicate a potential for protein binding by the carbodiimide group. However, it is questionable, if the carbodiimide group of this substance is accesible for skin proteins in vivo.